Rapid recognition of invading pathogens by the host organism is crucial in mounting an effective immune response. Conserved structural features on pathogens termed PAMPs are recognized by the Toll-like cell surface receptors, which are part of the evolutionary conserved innate immune system. Over a decade ago we co-discovered the activation of Interferon Regulatory Factor 3 (IRF3) by TLR ligands, and the ensuing induction of both, type I interferon genes (IFN?/?) and Interferon Stimulated Genes (ISGs). We subsequently characterized many components involved in TLR-mediated IRF3 and IRF7 activation and their role in both innate and adaptive immunity. Compelling evidence indicates that immunological events early after retroviral infection are critical determinants shaping the course of, for instance, HIV/AIDS disease. The innate immune response is an ancient defense system made up of functionally distinct subsystems that have evolved to counter infection by microbial pathogens including retroviruses such as HIV. The innate immune response is not antigen-specific, and is composed of the PAMP/TLR-induced interferon (IFN) system as well as cell-based anti-pathogen countermeasures that restrict the replication of pathogens. Understanding the innate immune response and the pathways that promote or restrict the kinetics of different steps of HIV infection is essential for devising novel pharmacological strategies for therapeutic intervention during these infectious disease processes, to develop diagnostic tools or to prevent infection. The current paradigm of the role of TLR3 and its downstream signaling components TRIF, TBK1 and IRF3/7 teaches that activation of this pathway during viral infection leads to the production of type I interferons, which in turn mediate their antiviral activity via the upregulation of ISGs. As such, this pathway is considered a cornerstone in the defense against RNA viruses, including retroviruses such as HIV. It was therefore a striking and unexpected finding that ablation of TLR3, TRIF or IRF7 lead to a dramatic reduction in HIV infection, rather than an enhancement. Similarly, pharmacological inhibition of TBK1, or the newly implicated polo-like kinases, as well as p300 abolished the completion of the HIV replication cycle. Interestingly, we found that the disruption of the TLR3->IRF7 pathway did not matter once the viral cDNA was integrated into the host cell genome. These observations lead us to the hypothesis that IRF7 activation downstream of TLR3/TRIF promotes generation, stability or integration of the viral cDNA, and that pharmacological inhibition this cascade at the very early stage after exposure to HIV has the potential to prevent the establishment of a viral reservoir similar to RT or integrase inhibitors, with the benefit of a limited likelihood of the emergence of drug resistance.